IGF-2 AUTOCRINE STIMULATION IN TUMORIGENIC CLONES OF A HUMAN COLON-CARCINOMA CELL-LINE

Clonal analysis has shown that the SW613-S human colon-carcinoma cell line is heterogeneous: some cell clones display a high level of amplif ication of the c-myc gene and are tumorigenic in nude mice, whereas ot hers have a small number of copies of this gene and are non-tumorigeni c. Tumorigenic clones can proliferate in a chemically defined serum-fr ee medium, whereas non-tumorigenic clones cannot. Suramin, like anti-i nsulin-like growth factor (IGF) or anti-IGF-1 receptor antibodies, eff iciently inhibits the growth of tumorigenic clones in defined medium. Inhibition by suramin or by anti-IGF antibodies can be reversed by pur e IGF-1 or IGF-2. Pure IGF-1 or IGF-2 or culture medium conditioned by tumorigenic clones can stimulate DNA synthesis in cells of non-tumori genic clones. Go-culture with cells of tumorigenic clones sustains the growth of non-tumorigenic clones in defined medium. Cells of both tum origenic and non-tumorigenic clones express high-affinity IGF-1 recept ors at their surface but tumorigenic clones produce on average 5 times more IGF-1 and 25 times more IGF-2 than non-tumorigenic ones. These r esults indicate that autocrine growth stimulation of tumorigenic clone s by IGFs through the IGF-1 receptor is essential for their ability to grow in defined medium. Since cells of tumorigenic clones produce IGF -2 at levels 80 times higher than IGF-1 and since an antibody strictly specific for IGF-1 has no effect on DNA synthesis in cells of tumorig enic clones grown in defined medium, IGF-2 is very likely the main eff ector in the autocrine loop. (C) 1995 Wiley-Liss, Inc.